The present invention relates to substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine adenosine A2a receptor antagonists, the use of said compounds in the treatment of central nervous system diseases, in particular Parkinson""s disease, and to pharmaceutical compositions comprising said compounds. The invention also relates to a process for preparing 5-amino-2-(substituted)pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines, intermediates useful in preparing the claimed compounds.
Adenosine is known to be an endogenous modulator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. On the respiratory system, adenosine induces bronchoconstriction. At the kidney level, it exerts a biphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets.
Adenosine action is mediated by the interaction with different membrane specific receptors which belong to the family of receptors coupled with G proteins. Biochemical and pharmacological studies, together with advances in molecular biology, have allowed the identification of at least four subtypes of adenosine receptors: A1, A2a, A2b and A3. A1 and A3 are high-affinity, inhibiting the activity of the enzyme adenylate cyclase, and A2a and A2b are low-affinity, stimulating the activity of the same enzyme. Analogs of adenosine able to interact as antagonists with the A1, A2a, A2b and A3 receptors have also been identified.
Selective antagonists for the A2a receptor are of pharmacological interest because of their reduced level of side affects. In the central nervous system, A2a antagonists can have antidepressant properties and stimulate cognitive functions. Moreover, data has shown that A2a receptors are present in high density in the basal ganglia, known to be important in the control of movement. Hence, A2a antagonists can improve motor impairment due to neurodegenerative diseases such as Parkinson""s disease, senile dementia as in Alzheimer""s disease, and psychoses of organic origin.
Some xanthine-related compounds have been found to be A1 receptor selective antagonists, and xanthine and non-xanthine compounds have been found to have high A2a affinity with varying degrees of A2a vs. A1 selectivity. Triazolo-pyrimidine adenosine A2a receptor antagonists with different substitution at the 7-position have been disclosed previously, for example in WO 95/01356; U.S. Pat. No. 5,565,460; WO 97/05138; and WO 98/52568.
The present invention relates to compounds having the structural formula I 
or a pharmaceutically acceptable salt thereof, wherein
R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or C4-C6 cycloalkenyl;
X is C2-C6 alkylene or xe2x80x94C(O)CH2xe2x80x94;
Y is xe2x80x94N(R2)CH2CH2N(R3)xe2x80x94, xe2x80x94OCH2CH2N(R2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94(CH2)2xe2x80x94NHxe2x80x94, or 
and
Z is R5-phenyl, R5-phenyl(C1-C6)alkyl, R5-heteroaryl, diphenylmethyl, R6xe2x80x94C(O)xe2x80x94, R6xe2x80x94SO2xe2x80x94, R6xe2x80x94OC(O)xe2x80x94, R7xe2x80x94N(R8)xe2x80x94C(O)xe2x80x94, R7xe2x80x94N(R8)xe2x80x94C(S)xe2x80x94, 
phenylxe2x80x94CH(OH)xe2x80x94, or phenyl-C(xe2x95x90NOR2)xe2x80x94; or when Q is 
Z is also phenylamino or pyridylamino; or
Z and Y together are 
R1 is 1 to 3 substituents independently selected from hydrogen, C1-C6-alkyl, xe2x80x94CF3, halogen, xe2x80x94NO2, xe2x80x94NR12R13, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, and C1-C6 alkylsulfonyl;
R2 and R3 are independently selected from the group consisting of hydrogen and C1-C6 alkyl;
m and n are independently 2-3;
Q is 
R4 is 1-2 substituents independently selected from the group consisting of hydrogen and C1-C6alkyl, or two R4 substituents on the same carbon can form xe2x95x90O;
R5 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, xe2x80x94CN, di-((C1-C6)alkyl)amino, xe2x80x94CF3, xe2x80x94OCF3, acetyl, xe2x80x94NO2, hydroxy(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-C6)alkoxy, di-((C1-C6)-alkoxy)(C1-C6)alkoxy, (C1-C6)-alkoxy(C1-C6)alkoxy-(C1-C6)-alkoxy, carboxy(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl(C1-C6)alkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, di-((C1-C6)alkyl)amino(C1-C6)alkoxy, morpholinyl, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-SOxe2x80x94(C1-C6)alkoxy, tetrahydropyranyloxy, (C1-C6)alkylcarbonyl(C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl, (C1-C6)alkylcarbonyloxy(C1-C6)-alkoxy, xe2x80x94SO2NH2, phenoxy, 
or adjacent R5 substituents together are xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CF2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CF2CF2xe2x80x94Oxe2x80x94 and form a ring with the carbon atoms to which they are attached;
R6 is (C1-C6)alkyl, R5-phenyl, R5-phenyl(C1-C6)alkyl, thienyl, pyridyl, (C3-C6)-cycloalkyl, (C1-C6)alkyl-OC(O)xe2x80x94NHxe2x80x94(C1-C6)alkyl-, di-((C1-C6)alkyl)aminomethyl, or 
R7 is (C1-C6)alkyl, R5-phenyl or R5-phenyl(C1-C6)alkyl;
R8 is hydrogen or C1-C6 alkyl; or R7 and R8 together are xe2x80x94(CH2)pxe2x80x94Axe2x80x94(CH2)q, wherein p and q are independently 2 or 3 and A is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94, and form a ring with the nitrogen to which they are attached;
R9 is 1-2 groups independently selected from hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halogen, xe2x80x94CF3 and (C1-C6)alkoxy(C1-C6)alkoxy;
R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, xe2x80x94CN, xe2x80x94NH2, C1-C6alkylamino, di-((C1-C6)alkyl)amino, xe2x80x94CF3, xe2x80x94OCF3 and xe2x80x94S(O)0-2(C1-C6)alkyl;
R11 is H, C1-C6 alkyl, phenyl, benzyl, C2-C6 alkenyl, C1-C6 alkoxy(C1-C6)alkyl, di-((C1-C6)alkyl)amino(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl or piperidino(C1-C6)alkyl;
R12 is H or C1-C6 alkyl; and
R13 is (C1-C6)alkyl-C(O)xe2x80x94 or (C1-C6)alkyl-SO2xe2x80x94.
Preferred compounds of formula I are those wherein R is R1-furanyl, R1-thienyl, R1-pyrrolyl or R10-phenyl, more preferably R1-furanyl. R1 is preferably hydrogen or halogen. Another group of preferred compounds is that wherein X is alkylene, preferably ethylene. Y is preferably 
wherein Q is 
with Q preferably being nitrogen. Preferably, m and n are each 2, and R4 is H. A preferred definition for Z is R5-phenyl, R5-heteroaryl, R6xe2x80x94C(O)xe2x80x94 or R6xe2x80x94SO2xe2x80x94. R5 is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R6 is preferably R5-phenyl.
Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier.
Yet another aspect of the invention is a method of treating central nervous system diseases such as depression, cognitive diseases and neurodegenerative diseases such as Parkinson""s disease, senile dementia or psychoses of organic origin, and stroke, comprising administering a compound of formula I to a mammal in need of such treatment. In particular, the invention is drawn to the method of treating Parkinson""s disease comprising administering a compound of formula I to a mammal in need of such treatment.
Another aspect of the invention is a process for preparing 5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines of formula II, which are intermediates useful in the preparation of compounds of formula I. The process of preparing compounds of formula II 
wherein R is as defined above, comprises
(1) treating 2-amino-4,6-dihydroxypyrimidine 
with POCl3 in dimethylformamide (DMF) to obtain 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde 
(2) treating carboxaldehyde VII with a hydrazide of the formula H2Nxe2x80x94NHxe2x80x94C(O)xe2x80x94R, wherein R is as defined above, to obtain 
(3) treating the intermediate of formula VII with hydrazine hydrate to form a pyrazolo ring, thus obtaining the intermediate of formula IX 
(4) forming the desired compound of formula II by dehydrative rearrangement.
A preferred aspect of the process is the dehydrative rearrangement of the intermediate of formula IX to obtain the 5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine of formula II. Preferred embodiments of the process use 2-furoic hydrazide or 2-thienoylhydrazide in step 2, thus preparing compounds of formula II wherein R is 2-furyl or 2-thienyl.
Another aspect of the invention is a process for preparing 7-bromoalkyl-5-amino-2-(R-substituted)-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines of formula IIIa, which are intermediates useful in the preparation of compounds of formula I. The process of preparing compounds of formula IIIa 
wherein R is as defined above, comprises
(1) treating a chloride of formula VIII 
with a hydroxyalkyl hydrazine of the formula HOxe2x80x94(CH2)rxe2x80x94NHNH2, wherein r is 2-6, to obtain 
(2) cyclizing the intermediate of formula X by dehydrative rearrangement to obtain the tricyclic intermediate of formula XI 
(3) converting the hydroxy compound of formula XI to the bromide of formula IIIa.
Still another aspect of the invention is a method of treating Parkinson""s disease with a combination of a compound of formula I and one or more agents known to be useful in the treatment of Parkinson""s disease, for example dopamine; a dopaminergic agonist; an inhibitor of monoamine oxidase, type B (MAO-B); a DOPA decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase (COMT) inhibitor.
Also claimed is a pharmaceutical composition comprising a compound of formula I and one or more agents known to be useful in the treatment of Parkinson""s in a pharmaceutically acceptable carrier.